Parenteral retinoid administration will be used to explore several aspects of the anti-carcinogenesis properties of retinoids in long-term attempts to understand mechanisms of abnormal differentiation. The model meets criteria of critical importance in the potential retinoid responsiveness of cells, namely, it achieves local tissue levels, without the systemic toxicity observed following conventional administration, with physiological rather than pharmacologic doses of the natural retinoid-the retinyl ester, retinyl palmitate-which can be hydrolyzed to the reported physiologically effective retinoid, retinol. The objective of the present proposal, which is an extension of the previous studies, is to identify mechanism(s) of action of retinoids by determining: (1) if their differentiation/anti-carcinogenic ability is correlated with their cellular uptake, transport, and distribution; (2) the regulatory role of lecithin-retinol acyltransferase (LRAT), a key enzyme in the esterification of retinol to retinyl :palmitate for storage. Light and electron microscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), electroelution, High Performance Liquid Chromatography (HPLC), radiobiochemistry, and autoradiography methods are used to evaluate lesions and after retinoid treatment. It is anticipated that this research will provide experimental evidence for basic mechanisms of abnormal differentiation and modulation by retinoids. The retinoid work is significant in that it represents a physiologic rather than cytotoxic approach to chemoprevention of carcinogenesis in epithelia that account for more than one-half of the total primary cancer in men and women.